Overexpression of multidrug resistance-associated protein 1 protects against cardiotoxicity by augmenting the doxorubicin efflux from cardiomyocytes.

Doxorubicin is a commonly used anti-cancer drug used in treating a variety of malignancies. However, a major adverse effect is cardiotoxicity, which is dose dependent and can be either acute or chronic. Doxorubicin causes injury by DNA damage, the formation of free reactive oxygen radicals and induction of apoptosis. Our aim is to induce expression of the multidrug resistance-associated protein 1 (MRP1) in cardiomyocytes derived from human iPS cells (hiPSC-CM), to determine whether this will allow cells to effectively remove doxorubicin and confer cardioprotection. We generated a lentivirus vector encoding MRP1 (LV.MRP1) and validated its function in HEK293T cells and stem cell-derived cardiomyocytes (hiPSC-CM) by quantitative PCR and western blot analysis. The activity of the overexpressed MRP1 was also tested, by quantifying the amount of fluorescent dye exported from the cell by the transporter. We demonstrated reduced dye sequestration in cells overexpressing MRP1. Finally, we demonstrated that hiPSC-CM transduced with LV.MRP1 were protected against doxorubicin injury. In conclusion, we have shown that we can successfully overexpress MRP1 protein in hiPSC-CM, with functional transporter activity leading to protection against doxorubicin-induced toxicity.

Development of new adeno-associated virus capsid variants for targeted gene delivery to human cardiomyocytes.

Recombinant adeno-associated viruses (rAAVs) have emerged as one of the most promising gene therapy vectors that have been successfully used in pre-clinical models of heart disease. However, this has not translated well to humans due to species differences in rAAV transduction efficiency. As a result, the search for human cardiotropic capsids is a major contemporary challenge. We used a capsid-shuffled rAAV library to perform directed evolution in human iPSC-derived cardiomyocytes (hiPSC-CMs). Five candidates emerged, with four presenting high sequence identity to AAV6, while a fifth divergent variant was related to AAV3b. Functional analysis of the variants was performed in vitro using hiPSC-CMs, cardiac organoids, human cardiac slices, non-human primate and porcine cardiac slices, as well as mouse heart and liver in vivo. We showed that cell entry was not the best predictor of transgene expression efficiency. The novel variant rAAV.KK04 was the best-performing vector in human-based screening platforms, exceeding the benchmark rAAV6. None of the novel capsids demonstrate a significant transduction of liver in vivo. The range of experimental models used revealed the value of testing for tropism differences under the conditions of human specificity, bona fide, myocardium and cell type of interest.

Promoter Optimization Circumvents Bcl-2 Transgene-Mediated Suppression of Lentiviral Vector Production.

Lentiviral vectors are a robust gene delivery tool for inducing transgene expression in a variety of cells. They are well suited to facilitate the testing of therapeutic candidate genes in vitro, due to relative ease of packaging and ability to transduce dividing and non-dividing cells. Our goal was to identify a gene that could be delivered to the heart to protect against cancer-therapy-induced cardiotoxicity. We sought to generate a lentivirus construct with a ubiquitous CMV promoter driving expression of B-cell lymphocyte/leukemia 2 gene (Bcl-2), a potent anti-apoptotic gene. Contrary to our aim, overexpression of Bcl-2 induced cell death in the producer HEK293T cells, resulting in failure to produce usable vector titre. This was circumvented by exchanging the CMV promoter to the cardiac-specific NCX1 promoter, leading to the successful production of a lentiviral vector which could induce cardioprotective expression of Bcl-2. In conclusion, reduced expression of Bcl-2 driven by a weaker promoter improved vector yield, and led to the production of functional cardioprotective Bcl-2 in primary cardiomyocytes.

In Search of Adeno-Associated Virus Vectors With Enhanced Cardiac Tropism for Gene Therapy.

Globally, adeno-associated virus (AAV) vectors have been increasingly used for clinical gene therapy trials. In Australia, AAV-based gene therapy is available for hereditary diseases such as retinal dystrophy or spinal muscular atrophy 1 (SMA1). Many preclinical studies have used AAV vectors for gene therapy in models of cardiac disease with outcomes of varying translational potential. However, major barriers to effective and safe therapeutic gene delivery to the human heart remain to be overcome. These include tropism, efficient gene transfer, mitigating off-target gene delivery and avoidance of the host immune response. Developing such an enhanced AAV vector for cardiac gene therapy is of great interest to the field of advanced cardiac therapeutics. In this review, we provide an overview of the approaches currently being employed in the search for cardiac cell-specific AAV capsids, ranging from natural AAVs selected as a result of infection and latency in the heart, to the use of cutting-edge molecular techniques to engineer and select AAVs specific for cardiac cells with the use of high-throughput methods.

Focal Anticoagulation by Somatic Gene Transfer: Towards Preventing Cardioembolic Stroke.

Cardioembolic stroke (CS) has emerged as a leading cause of ischaemic stroke (IS); distinguished by thrombi embolising to the brain from cardiac origins; most often from the left atrial appendage (LAA). Contemporary therapeutic options are largely dependent on systemic anticoagulation as a blanket preventative strategy, yet this does not represent a nuanced or personalised solution. Contraindications to systemic anticoagulation create significant unmedicated and high-risk cohorts, leaving these patients at risk of significant morbidity and mortality. Atrial appendage occlusion devices are increasingly used to mitigate stroke risk from thrombi emerging from the LAA in patients ineligible for oral anticoagulants (OACs). Their use, however, is not without risk or significant cost, and does not address the underlying aetiology of thrombosis and CS. Viral vector-based gene therapy has emerged as a novel strategy to target a spectrum of haemostatic disorders, achieving success through the adeno-associated virus (AAV) based therapy of haemophilia. Yet, thrombotic disorders, such as CS, have had limited exploration within the realm of AAV gene therapy approaches-presenting a gap in the literature and an opportunity for further research. Gene therapy has the potential to directly address the cause of CS by localised targeting of the molecular remodelling that serves to promote thrombosis.

Beyond Medical Care: How Different National Models of Care Impact the Experience of Adolescent and Young Adult Cancer Patients.

Patient experience is positively associated with clinical effectiveness, quality care, and patient safety. This study examines the experience of care of adolescents and young adult (AYA) cancer patients from Australia and the United States, allowing a comparison of patient experiences in the context of different national models of cancer care delivery. Participants (n = 190) were aged 15-29 years and received cancer treatment from 2014 to 2019. Australians (n = 118) were recruited nationally by health care professionals. U.S. participants (n = 72) were recruited nationally via social media. The survey included demographic and disease variables, and questions regarding medical treatment, information and support provision, care coordination, and satisfaction across the treatment pathway. Sensitivity analyses examined the possible contribution of age and gender. Most patients from both countries were satisfied or very satisfied with their medical treatment (chemotherapy, radiotherapy, and surgery). There were significant differences between countries in the provision of fertility preservation services, age-appropriate communication, and psychosocial support. Our findings suggest when a national system of oversight with both state and federal funding is implemented, as is the case in Australia but not in the United States, significantly more AYAs with cancer receive age-appropriate information and support services, and improved access to specialist services such as fertility care. A national approach with government funding and centralized accountability appears to be associated with substantial benefits for the well-being of AYAs undergoing cancer treatment.

Recombinant Adeno-Associated Viral Vector-Mediated Gene Transfer of hTBX18 Generates Pacemaker Cells from Ventricular Cardiomyocytes.

Sinoatrial node dysfunction can manifest as bradycardia, leading to symptoms of syncope and sudden cardiac death. Electronic pacemakers are the current standard of care but are limited due to a lack of biological chronotropic control, cost of revision surgeries, and risk of lead- and device-related complications. We therefore aimed to develop a biological alternative to electronic devices by using a clinically relevant gene therapy vector to demonstrate conversion of cardiomyocytes into sinoatrial node-like cells in an in vitro context. Neonatal rat ventricular myocytes were transduced with recombinant adeno-associated virus vector 6 encoding either hTBX18 or green fluorescent protein and maintained for 3 weeks. At the endpoint, qPCR, Western blot analysis and immunocytochemistry were used to assess for reprogramming into pacemaker cells. Cell morphology and Arclight action potentials were imaged via confocal microscopy. Compared to GFP, hTBX18-transduced cells showed that hTBX18, HCN4 and Cx45 were upregulated. Cx43 was significantly downregulated, while sarcomeric α-actinin remained unchanged. Cardiomyocytes transduced with hTBX18 acquired the tapering morphology of native pacemaker cells, as compared to the block-like, striated appearance of ventricular cardiomyocytes. Analysis of the action potentials showed phase 4 depolarization and a significant decrease in the APD50 of the hTBX18-transduced cells. We have demonstrated that rAAV-hTBX18 gene transfer to ventricular myocytes results in morphological, molecular, physiological, and functional changes, recapitulating the pacemaker phenotype in an in vitro setting. The generation of these induced pacemaker-like cells using a clinically relevant vector opens new prospects for biological pacemaker development.

Performance of Cardiotropic rAAV Vectors Is Dependent on Production Method.

Gene therapy is making significant impact on a modest, yet growing, number of human diseases. Justifiably, the preferred viral vector for clinical use is that based on recombinant adeno-associated virus (rAAV). There is a need to scale up rAAV vector production with the transition from pre-clinical models to human application. Standard production methods based on the adherent cell type (HEK293) are limited in scalability and other methods, such as those based on the baculovirus and non-adherent insect cell (Sf9) system, have been pursued as an alternative to increase rAAV production. In this study, we compare these two production methods for cardiotropic rAAVs. Transduction efficiency for both production methods was assessed in primary cardiomyocytes, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), and in mice following systemic delivery. We found that the rAAV produced by the traditional HEK293 method out-performed vector produced using the baculovirus/Sf9 system in vitro and in vivo. This finding provides a potential caveat for vector function when using the baculovirus/Sf9 production system and underscores the need for thorough assessment of vector performance when using diverse rAAV production methods.

Psychological, functional and social outcomes in adolescent and young adult cancer survivors over time: A systematic review of longitudinal studies.

OBJECTIVE: Most adolescents and young adults (AYA) can expect to survive a cancer diagnosis and treatment, but all will be left with the potential of long-term negative effects that can impact their ability to reach their full potential in life. Understanding aspects of psychological, functional, and social health and well-being outcomes, is pivotal for optimising long-term well-being. METHODS: We completed a systematic review of longitudinal studies reporting outcomes after anti-cancer treatment for Adolescents and Young Adults diagnosed between the age of 12-29 years according to established systematic review processes. The protocol was registered with PROSPERO (ID: CRD 42020203116). RESULTS: Thirteen reports from 10 studies met eligibility criteria representing 17,645 individuals (50.3% female, mean age at diagnosis 22 years, and 26 years at last, follow up). Eleven reports were from eight quantitative studies that relied on self-report surveys and two were qualitative studies. Psychological outcomes were reported to improve over time, as were functional health outcomes, although reported health behaviours were inconsistent between studies. Neurocognitive deficits were reported to affect the ability to return to work and impacts on fertility and sexuality were sustained over time. CONCLUSIONS: While some outcomes for AYA are reported to improve over time, particularly for physical functioning, and anxiety and depression, the long-term impact of cancer on many important domains remains largely unknown. Specifically, the evidence to understand what changes occur over time, and when, remains underdeveloped.

Potential Applications for Targeted Gene Therapy to Protect Against Anthracycline Cardiotoxicity: JACC: CardioOncology Primer.

Anthracyclines are associated with risk of significant dose-dependent cardiotoxicity. Conventional heart failure therapies have neither ameliorated declining cardiac function nor addressed the underlying cause. Gene therapy may confer long-term cardioprotection by rendering the heart resistant to anthracyclines after 1 treatment, although the optimal therapeutic target remains to be elucidated. Recombinant adeno-associated virus is now clinically approved for the treatment of lipoprotein lipase deficiency, spinal muscular atrophy, and hereditary transthyretin amyloidosis. High-throughput methods allow selection of recombinant adeno-associated virus capsids that facilitate efficient gene delivery to specific target cells. Vector safety is enhanced by incorporating cardiac-specific promoters into vector design and localizing delivery to reduce off-target risk. Any cardioprotective transgene may bear a degree of risk as they may play as yet unknown roles, which require careful assessment using clinically relevant models. The innovative technologies outlined here make gene therapy a promising proof of principle, with potential further application to nonanthracycline chemotherapeutics.

Gene and Cell Therapy for Cardiac Arrhythmias.

PURPOSE: In the last decade, interest in gene therapy as a therapeutic technology has increased, largely driven by an exciting yet modest number of successful applications for monogenic diseases. Setbacks in the use of gene therapy for cardiac disease have motivated efforts to develop vectors with enhanced tropism for the heart and more efficient delivery methods. Although monogenic diseases are the logical target, cardiac arrhythmias represent a group of conditions amenable to gene therapy because of focal targets (biological pacemakers, nodal conduction, or stem cell-related arrhythmias) or bystander effects on cells not directly transduced because of electrical coupling. METHODS: This review provides a contemporary narrative of the field of gene therapy for experimental cardiac arrhythmias, including those associated with stem cell transplant. Recent articles published in the English language and available through the PubMed database and other prominent literature are discussed. FINDINGS: The promise of gene therapy has been realized for a handful of monogenic diseases and is actively being pursued for cardiac applications in preclinical models. With improved vectors, it is likely that cardiac disease will also benefit from this technology. Cardiac arrhythmias, whether inherited or acquired, are a group of conditions with a potentially lower threshold for phenotypic correction and as such hold unique potential as targets for cardiac gene therapy. IMPLICATIONS: There has been a proliferation of research on the potential of gene therapy for cardiac arrhythmias. This body of investigation forms a strong basis on which further developments, particularly with viral vectors, are likely to help this technology progress along its translational trajectory.

Screening for atrial fibrillation and other arrhythmias in primary care.

BACKGROUND: Atrial fibrillation (AF) and other arrhythmias are prevalent and often encountered by general practitioners (GPs). In response to the growing prevalence and to assist practitioners in the diagnosis and management of AF, the Cardiac Society of Australia & New Zealand and Heart Foundation of Australia published the first Australian AF Guidelines in 2018. We aimed to examine (a) the proportion of GPs who performed any form of AF screening and identify the methods they applied, (b) GPs' awareness of the AF Guidelines and approaches to arrhythmia screening, (c) the roles of conventional 12-lead ECG and mobile health devices, and (d) GPs' confidence in ECG interpretation and need for training. METHODS: A cross-sectional online survey titled "GPs Screen their patients for Atrial Fibrillation and othEr aRrhythmia (GPSAFER)" was conducted from October 2018 to March 2019. The participants were recruited via various GP networks across Australia. Ethics approval was granted by The University of Sydney. RESULTS: A total of 463 surveys were completed. Many GPs (394/463, 85.1%, 95% CI 81.5-88.2%) performed some forms of AF screening and applied at least one AF screening method, most frequently pulse palpation (389/463, 84.0%). Some (299/463, 64.6%) GPs considered assessing their patients for other arrhythmias (237/299, 79.3% for complete heart block and 236/299, 78.9% for long-QT). Most GPs (424/463, 91.6%) were not using mobile ECG devices in their practice but some (147/463, 31.7%) were contemplating it. One third (175/463, 37.8%) of GPs were aware of the Australian AF Guidelines; those aware were more likely to perform AF screening (98.9% vs 76.7%, p <  0.001). Factors significantly and positively associated with AF screening were "awareness of the AF Guidelines" (p <  0.001), "number of years working in general practice" (p <  0.001), and "confidence in ECG interpretation of AF" (p = 0.003). Most GPs reported that they were very or extremely confident in interpreting AF (381/463, 82.3%) and complete heart block (266/463, 57.5%). Many GPs (349/463, 75.4%) would like to receive online ECG interpretation training. CONCLUSIONS: Assessment of arrhythmias is common in general practice and GPs are open to further training in ECG interpretation and using mobile ECG devices to aid their clinical practice. Increasing awareness of AF Guidelines and improving confidence in ECG interpretation may increase AF screening.

Analysis of recombinant adeno-associated viral vector shedding in sheep following intracoronary delivery.

Differences between mouse and human hearts pose a significant limitation to the value of small animal models when predicting vector behavior following recombinant adeno-associated viral (rAAV) vector-mediated cardiac gene therapy. Hence, sheep have been adopted as a preclinical animal, as they better model the anatomy and cardiac physiological processes of humans. There is, however, no comprehensive data on the shedding profile of rAAV in sheep following intracoronary delivery, so as to understand biosafety risks in future preclinical and clinical applications. In this study, sheep received intracoronary delivery of rAAV serotypes 2/6 (2 × 1012 vg), 2/8, and 2/9 (1 × 1013 vg) at doses previously administered in preclinical and clinical trials. This was followed by assessment over 96 h to examine vector shedding in urine, feces, nasal mucus, and saliva samples. Vector genomes were detected via real-time quantitative PCR in urine and feces up to 48 and 72 h post vector delivery, respectively. Of these results, functional vector particles were only detected via a highly sensitive infectious replication assay in feces samples up to 48 h following vector delivery. We conclude that rAAV-mediated gene transfer into sheep hearts results in low-grade shedding of non-functional vector particles for all excreta samples, except in the case of feces, where functional vector particles are present up to 48 h following vector delivery. These results may be used to inform containment and decontamination guidelines for large animal dealings, and to understand the biosafety risks associated with future preclinical and clinical uses of rAAV.

ITM support for patients with chronic respiratory and cardiovascular diseases: a protocol for a randomised controlled trial.

INTRODUCTION: Simple and scalable strategies are needed to improve 'out-of-hospital' support and management for people living with cardiovascular disease (CVD) and respiratory disease. Text messaging via mobile phones has been shown to be effective in helping promote lifestyle change and is supported by quantitative and qualitative evidence. The aim of this study is to test the effectiveness and implementation of a 6-month text messaging support programme for people with CVD and respiratory disease as an addition to cardiac and pulmonary outpatient rehabilitation. METHODS AND ANALYSIS: Pragmatic randomised controlled trial (n=310) to test the effectiveness of a 6-month text message support programme on clinical outcomes in people with CVD and chronic respiratory disease who are attending outpatient cardiac and pulmonary rehabilitation. The study includes a nested process evaluation to inform scalability and implementation across settings. The intervention group will receive a text message support programme comprising five messages per week for 26 weeks and the control group will continue with standard care. The primary outcome is exercise capacity (6 min walk distance). Secondary outcomes include clinical measures (proportion of people meeting the Australian guideline-recommended blood pressure and cholesterol targets), lifestyle outcomes (smoking rates, achievement of national guidelines for nutrition and physical activity), quality of life, mood (Hospital Anxiety and Depression Scale), medication adherence and attendance at and completion of rehabilitation. ETHICS AND DISSEMINATION: Primary ethics approval was received from the Sydney Local Health District Hospital Human Research Ethics Committee and associated Governance committees at sites. Results will be disseminated via the usual scientific forums including peer-reviewed publications and presentations at international conferences. At its conclusion, the study will determine the effectiveness and implementation of a simple programme that aims to improve health outcomes and attendance at rehabilitation for people with CVD and chronic respiratory disease. TRIAL REGISTRATION NUMBER: ACTRN12616001167459.

Effect of text messaging on depression in patients with coronary heart disease: a substudy analysis from the TEXT ME randomised controlled trial.

OBJECTIVE: We aimed to evaluate the effects on depression scores of a lifestyle-focused cardiac support programme delivered via mobile phone text messaging among patients with coronary heart disease (CHD). DESIGN: Substudy and secondary analysis of a parallel-group, single-blind randomised controlled trial of patients with CHD. SETTING: A tertiary hospital in Sydney, Australia. INTERVENTION: The Tobacco, Exercise and dieT MEssages programme comprised four text messages per week for 6 months that provided education, motivation and support on diet, physical activity, general cardiac education and smoking, if relevant. The programme did not have any specific mental health component. OUTCOMES: Depression scores at 6 months measured using the Patient Health Questionnaire-9 (PHQ-9). Treatment effect across subgroups was measured using log-binomial regression model for the binary outcome (depressed/not depressed, where depressed is any score of PHQ-9 ≥5) with treatment, subgroup and treatment by subgroup interaction as fixed effects. RESULTS: Depression scores at 6 months were lower in the intervention group compared with the control group, mean difference 1.9 (95% CI 1.5 to 2.4, p<0.0001). The frequency of mild or greater depressive symptoms (PHQ-9 scores≥5) at 6 months was 21/333 (6.3%) in the intervention group and 86/350 (24.6%) in the control group (relative risk (RR) 0.26, 95% CI 0.16 to 0.40, p<0.001). This proportional reduction in depressive symptoms was similar across groups defined by age, sex, education, body mass index, physical activity, current smoking, current drinking and history of depression, diabetes and hypertension. In particular, the rates of PHQ-9 ≥5 among people with a history of depression were 4/44 (9.1%) vs 29/62 (46.8%) in intervention vs control (RR 0.19, 95% CI 0.07 to 0.51, p<0.001), and were 17/289 (5.9%) vs 57/288 (19.8%) among others (RR 0.30, 95% CI 0.18 to 0.50, p<0.001). CONCLUSIONS: Among people with CHD, a cardiac support programme delivered via mobile phone text messaging was associated with fewer symptoms of mild-to-moderate depression at 6 months in the treatment group compared with controls. TRIAL REGISTRATION NUMBER: ACTRN12611000161921.

Neutrophils alleviate fibrosis in the CCl4-induced mouse chronic liver injury model.

Tribbles pseudokinase 1 (Trib1) is a negative regulator of CCAAT/enhancer binding protein α (C/EBPα) and is known to induce granulopoiesis while suppressing monocyte differentiation. Loss of Trib1 was previously shown to increase the neutrophil population in the spleen but lead to M2-like macrophage reduction. Because M2 macrophages are anti-inflammatory and promote tissue repair by producing fibrogenic factors, we investigated liver fibrosis in Trib1-deficient mice. Interestingly, loss of Trib1 suppressed fibrosis in the CCl4-induced chronic liver injury model. Trib1 knockout increased neutrophils but had a minimal effect on the macrophage population in the liver. Hepatic expressions of neutrophil matrix metalloproteinases (Mmp)8 and Mmp9 were increased, but the production of fibrogenic factors, including transforming growth factor ß1, was not affected by loss of Trib1. These results suggest that neutrophils are responsible for the suppression of fibrosis in Trib1-deficient liver. Consistently, transplantation of Trib1-deficient bone marrow cells into wild-type mice alleviated CCl4-induced fibrosis. Furthermore, expression of chemokine (C-X-C motif) ligand 1 (Cxcl1) by adeno-associated viral vector in the normal liver recruited neutrophils and suppressed CCl4-induced fibrosis; infusion of wild-type neutrophils in CCl4-treated mice also ameliorated fibrosis. Using recombinant adeno-associated virus-mediated expression of Mmp8 and Mmp9 alleviated liver fibrosis. Finally, neutrophil depletion by infusion of Ly6G antibody significantly enhanced CCl4-induced fibrosis. Conclusion: While neutrophils are well known to exacerbate acute liver injury, our results demonstrate a beneficial role of neutrophils in chronic liver injury by promoting fibrolysis. (Hepatology Communications 2018;2:703-717).

The transcription factor Klf5 is essential for intrahepatic biliary epithelial tissue remodeling after cholestatic liver injury.

Under various conditions of liver injury, the intrahepatic biliary epithelium undergoes dynamic tissue expansion and remodeling, a process known as ductular reaction. Mouse models defective in inducing such a tissue-remodeling process are more susceptible to liver injury, suggesting a crucial role of this process in liver regeneration. However, the molecular mechanisms regulating the biliary epithelial cell (BEC) dynamics in the ductular reaction remain largely unclear. Here, we demonstrate that the transcription factor Krüppel-like factor 5 (Klf5) is highly enriched in mouse liver BECs and plays a key role in regulating the ductular reaction, specifically under cholestatic injury conditions. Although mice lacking Klf5 in the entire liver epithelium, including both hepatocytes and BECs (Klf5-LKO (liver epithelial-specific knockout) mice), did not exhibit any apparent phenotype in the hepatobiliary system under normal conditions, they exhibited significant defects in biliary epithelial tissue remodeling upon 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced cholangitis, concomitantly with exacerbated cholestasis and reduced survival rate. In contrast, mice lacking Klf5 solely in hepatocytes did not exhibit any such phenotypes, confirming Klf5's specific role in BECs. RNA-sequencing analyses of BECs isolated from the Klf5-LKO mouse livers revealed that the Klf5 deficiency primarily affected expression of cell cycle-related genes. Moreover, immunostaining analysis with the proliferation marker Ki67 disclosed that the Klf5-LKO mice had significantly reduced BEC proliferation levels upon injury. These results indicate that Klf5 plays a critical role in the ductular reaction and biliary epithelial tissue expansion and remodeling by inducing BEC proliferation and thereby contributing to liver regeneration.

TEXT messages to improve MEDication adherence and Secondary prevention (TEXTMEDS) after acute coronary syndrome: a randomised clinical trial protocol.

BACKGROUND: Identifying simple, low-cost and scalable means of supporting lifestyle change and medication adherence for patients following a cardiovascular (CV) event is important. OBJECTIVE: The TEXTMEDS (TEXT messages to improve MEDication adherence and Secondary prevention) study aims to investigate whether a cardiac education and support programme sent via mobile phone text message improves medication adherence and risk factor levels in patients following an acute coronary syndrome (ACS). STUDY DESIGN: A single-blind, multicentre, randomised clinical trial of 1400 patients after an ACS with 12 months follow-up. The intervention group will receive multiple weekly text messages that provide information, motivation, support to adhere to medications, quit smoking (if relevant) and recommendations for healthy diet and exercise. The primary endpoint is the percentage of patients who are adherent to cardioprotective medications and the key secondary outcomes are mean systolic blood pressure (BP) and low-density lipoprotein cholesterol. Secondary outcomes will also include total cholesterol, mean diastolic BP, the percentage of participants who are adherent to each cardioprotective medication class, the percentage of participants who achieve target levels of CV risk factors, major vascular events, hospital readmissions and all-cause mortality. The study will be augmented by formal economic and process evaluations to assess acceptability, utility and cost-effectiveness. SUMMARY: The study will provide multicentre randomised trial evidence of the effects of a text message-based programme on cardioprotective medication adherence and levels of CV risk factors. ETHICS AND DISSEMINATION: Primary ethics approval was received from Western Sydney Local Health District Human Research Ethics Committee (HREC2012/12/4.1 (3648) AU RED HREC/13/WMEAD/15). Results will be disseminated via peer-reviewed publications and presentations at international conferences. TRIAL REGISTRATION NUMBER: ACTRN12613000793718; Pre-results.

The Role of Text Messaging in Cardiovascular Risk Factor Optimization.

PURPOSE OF REVIEW: Many cases of CVD may be avoidable through lowering behavioural risk factors such as smoking and physical inactivity. Mobile health (mHealth) provides a novel opportunity to deliver cardiovascular prevention programs in a format that is potentially scalable. Here, we provide an overview of text messaging-based mHealth interventions in cardiovascular prevention. RECENT FINDINGS: Text messaging-based interventions appear effective on a range of behavioural risk factors and can effect change on multiple risk factors-e.g. smoking, weight, blood pressure-simultaneously. For many texting studies, there are challenges in interpretation as many texting interventions are part of larger complex interventions making it difficult to determine the benefits of the separate components. Whilst there is evidence for text messaging improving cardiovascular risk factor levels in the short-term, future studies are needed to examine the durability of these effects and whether they can be translated to improvements in clinical care and outcomes.